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55. Cesko-Slovenské Farmakologické
dny 30.8.-1.9.2005, Hradec Králové
Evaluation of drug-drug interactions at the
level of hepatic excretion
Stanislav Micuda
Department of Pharmacology, Charles University in
Prague Faculty of Medicine in Hradec Králové
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55. Farmakologické dny
Hepatic drug processing
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Inhibition MDR1
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Induction MDR1
Greiner B J Clin Invest 1999104(2)147-53.
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In vivo
Preclinical - Clinical Studies

• Single and Repeat Dose Pharmacokinetics
• Drug Interaction Studies
• Mass Balance Excretion Studies
• Imaging Studies
• In Situ Tissue Perfusions

Mai I Clin Pharmacol Ther 200476(4)330-40. Saso
ngko L Clin Pharmacol Ther 200577(6)503-14.
99mTc-Sestamibi Scan following XR-9576
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55. Farmakologické dny
The aim of study
influence of dexamethasone on expression and
activity of mrp2
Dexamethasone
a synthetic corticosteroid, (t1/2 36-54 h),
eliminated mainly in the unchanged form in urine
induction of mrp2 protein expression?
Methotrexate (MTX) as a selective substrate for
mrp2 Probenecid as an inhibitor of mrp2
SPC 86698 DEXAMETHAZON LÉCIVA TBL
20X0.5MG-BLISTR LEX CZ
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55. Farmakologické dny
In vivo pharmacokinetics
Wistar male rats (Konárovice) - 3 groups (N 6)
? Dex (25 mg/kg daily 4 days, p.o.), Control
(Oliv. oil 4 days, p.o.), Probenecid ? 70
mmol/kg ? 3.33 mmol/min.kg-1 ?
simultaneously with MTX Clearance study ? left
jugular v. (MTX 22 mmol/kg ?164 nmol/kg.h-1? 4
ml/min) ? right a. carotis (blood sampling -
since 55 - 10 min) ? bladder (urine ? 0-90 min
? 10 min) ? bile duct (bile ? 0-90 min ? 10 min)
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55. Farmakologické dny
In vivo pharmacokinetics
MTX concentrations HPLC method with fluorescent
detection Farmacokinetic analysis
CLtotal Rinf / Css CLbil Cbil . Vbil /
Css CLren CU.VU / Css BE Cbil . Vbil
UE CU.VU CLRratio CLren / GFR CLRratioU
CLren / (fU .GFR) CLRS (CLren / fU) - GFR
Chladek J J Chromatogr B Biomed Sci Appl
2000744(2)307-13.
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Pharmacokinetics of MTX in steady-state
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Pharmacokinetics of MTX in steady-state
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Rat liver - mrp2 Dex per os
Dexametazon 25 mg/kg
Olive oil
BE ? 1.3-fold CLbile ?
1.1-fold Histol ? 3.1-fold Western ? 2.4-fold
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55. Farmakologické dny
Influence of DEX on P-gp activity
Pharmacokinetics of Rho-123
BE ? 2.2-fold CLbile ?
3.5-fold Histol ? 2.3-fold Western
? 2.8-foldReal RT-PCR ? 3.1-fold
Ctrl
DEX
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Conclusion

• Drug-drug interactions may be of great clinical
  importance
• - A significant number is transport
  protein-mediated
• in vivo studies a complex view of
  pharmacokinetics
• and mechanisms using model substrates
• in vivo studies verification of outcome from
  in vitro models
• allowing predictions
• - interspecies extrapolation
• Glucocorticoids and MRP2 vs. MTX
• induction of proteins without changes in
  pharmacokinetics of MTX

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55. Farmakologické dny
ACKNOWLEDGEMENTS
Co-workers Leoš Fuksa Jolana Cermanová Eva
Brcáková Jitka Hájková František Štaud Petr
Pávek Lucie Mundlová Jan Osterreicher Jaroslav
Mokrý Jaroslav Chládek Jirina Martínková
...enjoy adventure of every experiment...
Grants GAUK 89/2002/C MŠMT EC-B25.001